The long-term goal of this proposal is to reduce the adverse late effects of radiation therapy in normal CNS tissues to ultimately improve the quality of life and extend survival of patients with brain tumors. Radiation therapy is frequently used in patients with primary or metastatic brain tumors following surgical resection, or in diffused non-operable brain tumors. However, radiation therapy in the brain often leads to defects in neurocognitive functions, which limits the level of radiation doses that can be safely administered. Consequently, there is a critical need to reduce the late effects of radiation therapy in normal brain tissues. The cognitive impairments point to persistent defects in the hippocampus. Studies in animal models suggest that persistent oxidative stress, inflammation in the CNS, attrition of the dendritic networks, and reduced production of neurotrophic factors may contribute to deficits in learning and memory by hindering network connectivity and reducing the production of new neurons in the hippocampus. Based on these findings, we used a Mn porphyrin-based redox-active drug, MnBuOE, to suppress oxidative stress and a small molecule flavonoid compound, 7,8-dihydrxyflavone (7,8- DHF), to mimic the action of neurotrophic factors in cranial irradiation studies with mice. We found both drugs to increase the production of new neurons important for learning and memory, but each effected a different process of new neuron production. Whereas MnBuOE promoted the production of immature neurons, 7,8-DHF supported maturation and long-term survival of newborn neurons. Furthermore, 7,8-DHF treatment also led to preserved normal cognitive functions, dendritic spine densities, and synaptic proteins levels. The complementary actions of these two drugs leads us to hypothesize that combined treatment with MnBuOE and 7,8-DHF during different stages of radiation therapy may provide additive or synergistic effects in preserving normal cognitive functions. To test the hypothesis and examine the mechanisms underlying preserved cognitive functions from MnBuOE and 7,8-DHF treatment, we propose to (1) assess the impacts of MnBuOE and 7,8-DHF treatments on cognitive functions in young adult mice following cranial irradiation; (2) examine the effects of MnBuOE and 7,8-DHF treatments on cognitive functions in middle-aged mice following cranial irradiation; (3) investigate the effects of MnBuOE and 7,8-DHF treatments on inhibitory neurons in middle-aged mice following cranial irradiation; and (4) examine how combined treatments of MnBuOE, 7,8-DHF, and cranial irradiation affect the growth or survival of glioblastoma. Non-tumor bearing mice will be treated with different combinations of MnBuOE and 7,8-DHF before and after cranial irradiation. Behavioral, immunohistochemical, biochemical, and molecular biological approaches will be used to investigate changes in cognitive functions, dendritic structures, neuroinflammation, and synaptic plasticity. Electrophysiology methods will be used to examine the function of fast spiking parvalbumin positive (PV+) interneurons in the hippocampus to better understand the impact of radiation on this neuronal population. A xenograft model will be used to examine the effects of MnBuOE and 7,8- DHF on tumor growth and host survival following cranial irradiation. Successful completion of the proposed studies will help to establish a new treatment combination that can effectively decrease or reverse the adverse effects of cranial irradiation on neurocognitive functions without necessarily reducing the efficacy of radiation- mediated tumor suppression. As a result of preserved cognitive functions, the new treatment combination may increase the efficacy of radiation therapy by allowing higher doses of radiation that can be safely administered for cancer treatment.